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Contrast echocardiography in critical care: echoes of the future? A review of the role of microsphere contrast echocardiography

David G Platts and John F Fraser

Crit Care Resusc ISSN: 1441-2772 1 March2011 13 1 44-55© C r i t Ca r e Re sus c 2 011www.jficm.anzca.edu.au/aaccm/journal/publi-cations.htmReview

ing conditions, inability to position the patient the imaging, and surgical sites/drains preventingof conventional echocardiographic views.2,3 Thpoor endocardial definition and hence inaccurtion of left ventricular (LV) function (both regional) and morphology. Although transo

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ABSTRACT

Echocardiography is an important diagnostic modality in the critical care setting. It is a safe, non-invasive bedside investigation that provides important cardiac structural, functional and haemodynamic information. However, in up to 25% of scans, the images are non-diagnostic, which can have a significant impact on patient diagnosis and management. Contrast echocardiography, using contrast microspheres coupled with contrast-specific ultrasound imaging modalities, overcomes many of the limitations that cause suboptimal echocardiograms in the critical care environment. These microspheres are haemodynamically inert and have the same intravascular rheology as red blood cells. By using the differential oscillating properties of myocardium and microspheres, contrast echocardiography can enhance the blood pool–myocardial interface, thus improving endocardial definition. Consequently, this technique can be used to improve the accuracy, feasibility and reproducibility of transthoracic echocardiography. The technique is well accepted and indicated for improving the image quality in suboptimal scans, and for the assessment of global and regional left ventricular (LV) function and LV ejection fraction. It also has a significant role to play in enhancing LV morphology (for conditions such as apical hypertrophic cardiomyopathy, pseudoaneurysm and non-compaction), assessing intracardiac masses and evaluating LV thrombus. Contrast echocardiography is of benefit in various clinical settings, particularly the critical care setting. Here it can salvage a non-diagnostic transthoracic echocardiogram, thus avoiding an alternative, more invasive investigation, while remaining a truly bedside, non-invasive investigative procedure. Future applications for contrast echocardiography could include use as a perfusion modality, enhancement of three-dimensional echocardiography, and

Crit Care Resusc 2011; 13: 44–55

targeted delivery of gene therapy.

Transthoracic echocardiography (TTE) is an important imag-ing modality in clinical cardiology and critical care medicine.It provides information that helps in diagnosis and influ-ences patient management, as well as providing importantprognostic information. Cardiac anatomical and physiologi-cal parameters are obtained using a non-invasive, safe andwell tolerated technique. However, in up to 25% of cases ofstudies performed in the critical care setting, suboptimalimages are obtained.1

Patients in the intensive care unit generally present thegreatest technical challenge for obtaining diagnostic tran-sthoracic images. Reasons for this include the patient’sbeing supine and mechanically ventilated, suboptimal light-

to optimise acquisitionis results inate evalua-global andesophageal

echocardiography (TOE) can be used to obtain diagnosticimages, it necessitates deep sedation, which may precludeits use in the non-intubated patient with respiratory dys-function, oesophageal pathology and other comorbidities.

Contrast-enhanced TTE (CE) is a safe and non-invasiveimaging technique that can overcome these limitations,even in unstable patients who cannot be moved from the

Abbreviations

CE Contrast-enhanced TTE

ECG Electrocardiogram

ECMO Extracorporeal membrane oxygenation

EF Ejection fraction

FDA (US) Food and Drug Administration

FE Fundamental TTE

HE Harmonic TTE

LV Left ventricular

LVO Left ventricular opacification

MCE Myocardial contrast echocardiography

MI Mechanical index

RVSP Right ventricular systolic pressure

SE Standard TTE

TOE Transoesophageal echocardiography

TTE Transthoracic echocardiography

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ICU. This review provides staff in thecritical care setting with informationabout contrast imaging modalities,agents available, indications, con-traindications, safety, and futureapplications of the technique.

Contrast agents

The term “contrast echocardiogra-phy” can refer to several forms ofechocardiography, but this reviewfocuses on microsphere contrastechocardiography. Contrast echocar-diography can also refer to the simpleadministration of agitated saline toassess for right-to-left shunts. In thistechnique, normal saline is agitatedand injected into a peripheral venouscannula during conventional TTEimaging. These agitated saline bub-bles are typically 50–90 μm in diame-ter and have a very short half-life. Thisbasic technique is useful to determinewhether there is an intrapulmonary orintracardiac right-to-left shunt.

Microsphere contrast echocardiog-raphy (MCE) is a different entity andutilises microbubbles during contrast-specific echocardiographic imagingmodalities to enhance the blood pooland improve the blood–myocardialinterface. After administration into aperipheral venous cannula, the con-trast microspheres pass through theright heart, enter the pulmonary cir-culation and flow to the left heart,thereby increasing ultrasound backscatter of the bloodpool. The following section will explain the ultrasoundprinciples involved in this technique.

The different ultrasound contrast agents currently availa-ble or under development are all based on a similarstructural principle: they have an outer shell and innergaseous core. It is the composition of these two compo-nents that makes each agent unique, both in its response toultrasound waves and in its clinical utility. The microbubblesneed to be sufficiently elastic to resonate in response toultrasound, but sufficiently robust to survive passagethrough the giving sets and the pulmonary circulation.

Echocardiographic contrast agents can be classified asfirst-generation, second-generation or third-generation(novel/custom-made bubbles). The first-generation bub-

bles had a basic structure, with airas their gaseous core. First-genera-tion agents included sonicated albu-min (Albunex) and Levovist. Second-generation agents have a morecomplex structure, with a high-molecular-weight gaseous core.Currently available second-genera-tion agents are Optison (GE Health-care, Amersham, UK), SonoVue(Bracco Diagnostics, Milan, Italy)and Definity (Lantheus MedicalImaging, Billerica, Mass, USA).Novel (third-generation) contrastagents are custom-made for a par-ticular purpose, either for therapy orfor a particular type of imaging.

Definity (perflutren microspheres)is the second-generation agentapproved for use and marketed inAustralia. Definity microspheres havea mean diameter of 3 μm and consistof a gaseous core and a lipid shell.The gaseous core is a high-molecu-lar-weight gas called octafluoropro-pane (MW = 188). This biologicallyinert gas is encapsulated in a trilipidshell. In the unactivated form (leftpanel image in Figure 1), it consistsof the clear liquid lipid shell belowand the gaseous core above. Itrequires activation in a VialMix (Lan-theus Medical Imaging, Billerica,Mass, USA) device (Figure 2), whichagitates the ampoule at 4530 ± 100oscillations per minute for 45 sec-onds. This generates a solution of

perflutren microsphere bubbles, which have an opaque,milky white appearance (right panel image in Figure 1).Activation produces 1.3 mL of contrast agent with thefollowing properties:4

• Microsphere concentration1.2 � 1010/mL;• Microsphere mean diameter 3 μm;• Size distribution 98% < 10 μm;• Maximum diameter 20 μm;• pH 5.8–7.0.

Pharmacokinetics

After Definity has been administered, it provides 3–5 minutesof contrast signal persistence before the bubbles lose theirstructure and hence no longer produce ultrasound backscat-

Figure 1. Unactivated (left) and activated (right) Definity contrast agent

Figure 2. VialMix device for activating contrast agent

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ter. The octafluoropropane gas is not metabolised and isexcreted unchanged in the lungs. The mean half-life is 1.3minutes in healthy subjects and 1.9 minutes in people withchronic airflow limitation. The lipid shell is metabolised by theusual process of fatty acid metabolism.

Other contrast agents

Two other commercially available contrast agents are availa-ble outside Australia, Optison and SonoVue. Optison has anoctafluoropropane gaseous core and a 1% human albuminshell. It requires no preparation other than hand agitationand dilution with normal saline. SonoVue has a gaseouscore of sulfur hexafluoride (SF6) and a phospholipid shell.The agent is reconstituted with 5 mL of normal saline andhand agitated for 20 seconds.

Additional agents are undergoing research and develop-ment, with a view to using them as possible perfusionagents or for targeted delivery of gene therapy.

Contrast-specific imagingContrast imaging employs techniques that are specific tomicrobubble imaging. Imaging of these bubbles with con-ventional modes results in excessive bubble destruction andnon-diagnostic images. Figure 3A shows a contrast imageobtained with conventional TTE imaging, and Figure 3B isthe same view with contrast-specific imaging activated. Asdemonstrated, a high transmit power (typically with amechanical index [MI] above 1.0 during conventional imag-ing) destroys microbubbles. Thus, low-transmit powerimaging modalities had to be developed.

Contrast agent microbubbles have a greater harmonicsignal than tissue. However, in early experimentation withthese agents, the presence of tissue harmonics confoundedthe issue and reduced the discrimination between thecontrast agent and tissue. This resulted in the need todevelop specific techniques to maximise the contrast signalwhile minimising the tissue signal (or enhancing the con-trast-to-tissue signal ratio). These are multipulse, real-timeimaging techniques based on three important concepts thatare key to microbubble imaging:• Mechanical index;• Oscillation properties of tissue and microbubbles:

Tissue with linear oscillation;Microbubbles with non-linear oscillation; and

• Effect of microbubble size.The MI is a measure of the acoustic output power of the

ultrasound system. It is an indicator of the non-thermalbioeffect of ultrasound waves. It can also be defined as ameasure of the negative acoustic pressure within theultrasound field. The MI is quoted as a single, unitlessnumber. In conventional, two-dimensional echocardio-graphic scanning, it is typically around 1.4.5 However, theMI during contrast-specific imaging is significantly lower, inthe order of 0.1–0.3.

In low-MI imaging, myocardial tissue and contrast micro-bubbles have significantly different backscattering proper-ties. By exploiting this difference, contrast imaging modescan enhance the contrast signal while suppressing themyocardial signal, with the net result of enhancing theendocardial border. At low MI, tissue (myocardium) acts as alinear reflector (or backscatterer) of ultrasound energy. Assuch, if P level of energy (MI) is directed at the myocardium,then T amplitude response will be received. Furthermore, if2P of energy is then directed at the myocardium, then 2T(double the initial response) will be returned.

However, contrast agents behave significantly differentlyto tissue in a low-output power ultrasound field. At lowMI, contrast microbubbles demonstrate a non-linear oscil-lation response to exposure to an ultrasound wave. Theyexpand more than they contract and there is a differencein the phase of the response. The higher the transmit

Figure 3. Transthoracic echocardiographic images of contrast being imaged without (A) and with (B) contrast-specific imaging activated

A: Conventional imaging.

B: The same view with contrast-specific imaging activated.

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power, the greater the difference in expansion and con-traction of the microbubbles and hence the greater thenon-linearity of the signal response (Figure 4).

Each of the ultrasound vendors has its own specific formof contrast-specific imaging, using modulation of eitherultrasound amplitude or phase or both. Power modulationimaging using a Philips iE33 scanner (Philips UltrasoundSystems, Andover, Mass, USA) is one such example. It is amultipulse technique that sends two pulses down eachscan line. The two transmit pulses are of different ampli-tude, one at full amplitude and one at half amplitude. Theprocessor transiently stores the received signals. Thereturning signal from the full-strength pulse is labelled T,and the other signal (originating from the half-strengthpulse) is labelled ½T. The processor generates a final signalby doubling the half-strength signal (½T) and then sub-tracting this from the returning signal from the full-strength pulse (T). Doubling a half-strength signal andsubtracting this from a full-strength signal from a myocar-dial image results in cancellation of these signals, as tissueis a linear reflector. That is, the echoes received from thefull- and half-amplitude pulses are just scaled copies ofone another. The net result is that the myocardium issuppressed and essentially appears black in the absence ofany contrast signal. However, as contrast microbubbles arenon-linear reflectors, the returning signals are not scaledimages of each other; they are slightly out of phase andare not scaled copies of each other. Doubling the transmitpower will result in a greater than doubled received echoamplitude. Thus, when the doubled half-amplitude signalis subtracted from the full-amplitude signal, they do notcancel out. The net result is that a contrast signal isgenerated.

The final image generated depends on whether thesignal is coming from linear, non-oscillating tissue or non-linear, oscillating contrast microbubbles. Figure 5A showsthe best possible image obtained using tissue harmonic

imaging in a supine, ventilated patient in the ICU. Figure5B shows the same view in the same patient afteradministration of a contrast agent during contrast-specificimaging. Note the significantly improved endocardial defi-nition and anterolateral papillary muscle.

Microbubble size is also a crucial factor in contrastimaging. For an intravenous agent to reach the coronarycirculation, it has to be small enough to pass through thepulmonary circulation. That is, the microbubbles essen-tially have to be the same size as red blood cells. Thebubble size determines their resonant frequency. Thebackscattering property of a bubble is proportional to the6th power of its radius. Hence, the largest bubble that willcross the pulmonary circulation will result in a superioracoustic signal.6 Fortunately, contrast agents that have asize enabling them to cross the pulmonary circulation alsoresonate at a frequency that is used in conventionalmedical imaging (1.5–7 MHz).7

Figure 5. Apical four-chamber images taken in a supine, ventilated patient in the intensive care unit

A: Best possible image obtained using conventional tissue harmonic imaging.

B: The same view with contrast-enhanced imaging (arrow indicates anterolateral papillary muscle).

Figure 4. Backscattering properties of myocardium and contrast microbubbles at low mechanical index

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Contrast agent preparation and administration

The Definity contrast agent is presented in a glass vial andrequires storage in a refrigerator (at around 4° C). Beforeadministration, it is activated by agitation, using the VialMixdevice, into a suspension of microbubbles. After prepara-tion, the solution is withdrawn from the ampoule (using aventing needle) and diluted with normal saline to either10 mL (for bolus dosing) or 50 mL (for an infusion).

Contrast indications and clinical applications

Limitations of TTE, particularly in the critical care setting,can result in suboptimal cardiac imaging. The use ofcontrast agents has proved beneficial by improving thedefinition of the endocardial border in suboptimal studies.This form of contrast imaging, called LV opacification (LVO),results in improved assessment of LV structure and function.It is an accurate and reproducible technique, both forresting and stress echocardiography.8-20 LVO imaging hasalso been assessed in the critical care setting, where it has

been shown to be safe, feasible and comparable to tran-soesophageal echocardiographic assessment of LV regionaland global function.1,2,21-25

In light of the extensive data supporting the use ofcontrast to improve LVO, regulatory authorities (such asthe United States Food and Drug Administration [FDA],European Medicines Agency and the Australian Therapeu-tic Goods Administration) have approved its use in situa-tions where conventional TTE is suboptimal or non-diagnostic. Both the American Society of Echocardiogra-phy and the European Association of Echocardiographyhave recently issued position papers and consensus state-ments regarding the clinical application of CE.6,26 Thefollowing are accepted indications for the use of contrastto improve the diagnostic yield of echocardiography:• To improve assessment of LV structure and function

when two or more continuous segments are not seenon unenhanced imaging (both for resting and stressechocardiography);

Figure 6. Ventricular trabeculation

A: Best possible image obtained using conventional tissue harmonic imaging.

B: The same view with contrast-specific imaging. Note the prominent trabeculation in the left ventricular lateral wall.

Figure 7. Apical four-chamber images: left ventricular (LV) thrombus

A: Conventional imaging.

B: The same view with contrast-specific imaging, clearly delineating the LV apical thrombus that was not detected with conventional imaging (arrow).

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• To improve assessment, confidenceand reproducibility of LV volumesand ejection fraction (EF); and

• To improve assessment of LV mor-phology in the following situationsin which unenhanced imaging isnon-diagnostic:

LV non-compaction (non-com-paction cardiomyopathy);Apical hypertrophic cardiomy-opathy;LV thrombus;LV pseudoaneurysm formation.

Figure 6A represents the best possi-ble image obtained with conventional,tissue harmonic imaging. Figure 6B isthe same image with contrast-specificimaging. Note the prominent trabecu-lation in the LV lateral wall.

There are other clinical uses of CE inwhich contrast enhancement has beenfound to be beneficial but where theevidence base is weaker. These indica-tions include:• Assessment of cardiac masses;27-34

• Enhancement of spectral Dopplersignals;20,35

• Assessment of aortic dissection;36-38

and• Assessment of femoral artery pseu-

doaneurysm.39

Figure 7A shows an unenhancedapical four-chamber view to assess forLV thrombus. Figure 7B represents thesame view with contrast-specific imag-ing, clearly delineating the LV apicalthrombus that was not detected withconventional imaging.

Figure 8A shows an unenhancedapical four-chamber TTE image. Figure8B is a contrast-enhanced apical four-chamber TTE image demonstrating anLV pseudoaneurysm (as measured).Figure 8C shows the correspondingview with a cardiac magnetic reso-nance image, confirming the pseu-doaneurysm.

Application of contrast LVO in critical care

Echocardiography is integral to the assessment and man-agement of patients in the critical care setting. It provides a

rapid, safe, non-invasive, completeand accurate assessment of cardiacstructure and function. One of theother key benefits of TTE is that it is abedside test within the critical carecomplex. There is no need to move ortransfer a patient for this investiga-tion. It can be performed on criticallyill patients with a wide range of com-plex conditions. Its use in critical care isendorsed within societal guidelines onappropriateness criteria.40 Due to thecomplex problems of patients in criti-cal care, they have the most to gainfrom accurate and reliable assessmentof cardiac structure and function.However, they can also present thegreatest challenge in obtaining diag-nostic TTE images. If TTE does notprovide satisfactory diagnostic infor-mation on cardiac structure or func-tion, TOE or a right heart catheter maybe required to obtain the necessaryinformation.

Although accurate, these investiga-tions are limited by being invasive,time-consuming, costly and moreuncomfortable for the patient. In anon-ventilated patient, TOE will alsorequire sedation. In critically ill patientswith limited cardiopulmonary reserve,this sedation could precipitate theneed for intubation and ventilation.CE has the ability to improve diagnos-tic accuracy of suboptimal unen-hanced TTE, and hence to avoid theneed for these other investigations.

However, the incremental benefit ofadministering a contrast agent withTTE can be dependent on the indica-tion. Contrast enhancement is notbeneficial for assessing valvular struc-ture or function (except for spectralDoppler enhancement). For example,echocardiographic assessment forinfective endocarditis is not enhancedby using contrast. For these indica-tions, TOE is still required to obtain thenecessary information.

In a prospective study of 70 unselected patients in anICU, Reilly and colleagues assessed LV wall motion and LVEFusing standard TTE (SE), harmonic TTE (HE) and CE.1 There

Figure 8. Apical four-chamber images: left ventricular (LV) pseudoaneurysm

A: Conventional imaging.

B: The same view with contrast-enhanced imaging, showing an LV pseudoaneurysm (as measured) (arrow).

C: The same view with cardiac magnetic resonance imaging, confirming the presence of a pseudoaneurysm (arrow).

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was a significantly higher mean number of uninterpretablesegments using SE and HE compared with CE (5.4 v 4.4 v1.1, respectively; P < 0.001 for HE v CE). The LVEF wasuninterpretable in significantly more cases with unen-hanced imaging (23% for SE, 13% for HE and 0% for CE;P = 0.002 for CE v HE; P < 0.001 for CE v SE). Scoringconfidence for LV wall motion was also significantly betterwith CE than with unenhanced imaging (56% for SE, 62%for HE and 91% for CE; P = 0.47 for SE v HE; P < 0.001 forHE v CE). This study highlights how frequently conventionalTTE is non-diagnostic in the critical care setting and showsthat contrast enhancement can result in increased imagequality and confidence in assessment of LVEF.

Figure 9A shows an unenhanced apical four-chamber TTEimage with an echo density at the apex, suggestive of an LVapical thrombus. Figure 9B is a contrast-enhanced apical

four-chamber TTE image, revealing that the apical echodensity is due to extensive LV apical trabeculation (arrows),a common mimicker of apical thrombus in unenhancedimaging.

In an important study, Yong and colleagues assessed theaccuracy and cost-effectiveness of CE in technically difficultstudies in the ICU.21 Fundamental TTE (FE), HE and CE wereperformed in 32 patients with poor images and comparedwith TOE. Adequate or good endocardial definition wasobtained in 13% of segments using FE, 34% with HE and87% with CE (P < 0.001). There was no significant differ-ence between CE and TOE (87% v 90%; P = ns). LVEF wasinterpretable in 31% of cases with FE, 50% with HE and91% with CE. LVEF calculated using CE correlated best withTOE (r = 0.91). Additionally, the study sought to assess thecost-effectiveness of CE. Compared with TOE, CE was cost-effective in assessing regional and global LV systolic func-tion, with cost savings of 3% and 17%, respectively. Similarresults, showing a benefit of contrast-enhanced imaging inthe critical care setting, have been demonstrated by Cohenet al,41 Makaryus et al,22 Kornbluth et al,2 Daniel et al,3

Nguyen et al42 and Costa et al.23

The impact and outcome of improved image quality (akey component of assessing the benefit of a new form ofimaging) was addressed in a recent study by Kurt et al.24 Inthis study, 632 patients with suboptimal TTE images wereprospectively enrolled and administered a contrast agent.Image quality and the impact on clinical management wereassessed before and after administration of the contrastagent. The mean numbers of LV segments seen before andafter contrast imaging were 11.6 ±3.3 and 16.8 ±1.1,respectively (P < 0.001). Additionally, the number of TTEstudies that were uninterpretable was reduced from 11.7%pre-contrast to 0.3% post-contrast (P < 0.001). Contrastwas also beneficial in LV thrombus assessment. Beforecontrast was added, there were 35 suspected and threedefinite thrombi. After addition of contrast, only onepatient remained with a suspected thrombus and anotherfive had confirmed thrombi (P < 0.001). The cost-effective-ness of CE was also assessed in this study. With respect tothe cost of diagnostic procedures alone, CE resulted in asaving of $122 per patient (and this did not take intoaccount other potential cost benefits of altering or correct-ing medical therapy).

However, the key aspect of the study by Kurt et al wasthe impact that CE had on patient management. As a resultof improvement in image quality, CE averted the need forfurther diagnostic procedures in 207 patients (32.8%) (140resting gated heart pool scans and 67 transoesophagealechocardiograms). When patients in the critical care settingwere analysed, the impact of CE was even greater, with55% of patients in the surgical ICU and 33% of patients in

Figure 9. Apical four-chamber images: suspected left ventricular (LV) thrombus

A: Conventional imaging showing an echo density at the apex, suggestive of an LV apical thrombus.

B: The same view with contrast-enhanced imaging, revealing that the apical echo density is due to extensive LV apical trabeculation, a common mimicker of apical thrombus in unenhanced imaging (arrows).

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the medical ICU having a potential further diagnosticprocedure avoided. With respect to patient management,the results of CE altered medical treatment in 67 cases(10.6%). Again, when patients in the critical care settingwere assessed, the impact on patient treatment was evengreater, with 25.5% in the surgical ICU and 8.9% in themedical ICU having an alteration in medical therapy basedon CE results. Together, a total of 225 patients (35.6%) hadan alteration in diagnostic procedure or treatment based onCE results. The greatest impact was in the critical caresetting, with changes of 62.7% and 41.9% for surgical andmedical ICU patients, respectively. As expected, the likeli-hood of contrast imaging altering management was relatedto the number of segments poorly visualised on TTE. Inpatients with more than 12 segments poorly visualised,contrast imaging had an impact on management in 93.6%.For those with 2–6 segments poorly visualised, contrastimaging results influenced management in 14.2%(P < 0.001).

Figure 10 shows a CE image of a large LV apical thrombusin a patient with cardiogenic shock due to coronary arterydisease. The patient was being supported with venoarterialextracorporeal membrane oxygenation (ECMO).

Contrast agent safety and contraindications

Echocardiography using contrast agents is a safe procedure.Quoted adverse reactions are headache (2%), back pain orflushing (1%) (both of which resolve as soon as administra-tion of contrast agent is stopped), and a 1 in 10 000 risk ofanaphylaxis. Contraindications to the use of Definity areknown or suspected right-to-left cardiac shunts, hypersensi-tivity to perflutren, and direct intra-arterial injection.4 Exten-sive data indicate that Definity has an excellent safetyprofile and that there is no increased morbidity or mortalityassociated with its use.26,43-55 After administration, there isno change in pulmonary or systemic haemodynamics,ventricular function, gas exchange or myocardial bloodflow, and no increase in major adverse cardiac events ormortality. Contrast microspheres act as biologically inert,pure blood flow tracers and are not taken up by cells ormetabolised by mitochondria.

However, in October 2007, the FDA issued a “black box”warning for contrast agents, following four deaths withinhalf an hour of patients receiving contrast agents. To putthis in context, contrast agents had been in clinical use forover 10 years and had been used in over two million cases.Extensive evaluation of this decision resulted in the conclu-sion that these cases reflected a “pseudo-complication”,where there was a temporal but not causal association withthe deaths. After further extensive work and analysis ofthese cases, in May 2008, the FDA significantly down-

graded its concerns. This related to both contraindicationsto administration and requirements for monitoring afterdosing. The current recommendation of the FDA is that if apatient has an unstable cardiopulmonary condition orpulmonary hypertension (severity not stated), the patientshould be monitored (vital signs, electrocardiogram, oxygensaturations) for 30 minutes after administration of a con-trast agent.45

Although the FDA has stated that closer monitoring ofpatients with pulmonary hypertension is required, there areno data to guide the clinician as to what pulmonarypressure precludes administration of a contrast agent. Thelevel has not been stipulated by the FDA. To help resolvethis issue, Abdelmoneim and colleagues have recentlyreported on a large retrospective trial assessing the effect ofcontrast agent administration in patients with pulmonaryhypertension.54 The authors assessed 26 774 patientsundergoing stress echocardiography. Right ventricularsystolic pressure (RVSP) was calculated in 16 434 patients,of whom 6164 received a contrast agent and 10 270 didnot. RVSP cut-off points were � 35 mmHg, � 50 mmHgand � 60 mmHg. Endpoints were short-term (� 72 hoursand � 30 days) and long-term (4.3 years) death andmyocardial infarction. The patients who received contrastagents were older and more likely to have a positive stressecho result. Despite this, there was no significant differencein short- or long-term events between patients whoreceived a contrast agent and those who did not.

In another landmark study, Exuzides and colleaguesevaluated mortality among critically ill patients undergoingechocardiography with and without contrast.55 In this

Figure 10. Contrast-enhanced transthoracic echocardiogram, showing a large LV apical thrombus in a patient with cardiogenic shock due to coronary artery disease and supported on venoarterial ECMO

ECMO = extracorporeal membrane oxygenation. LV = left ventricular.

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retrospective review, 2900 patients with critical illness whoreceived CE were compared with 11 600 patients withcritical illness who did not. Propensity score matching wasused to control for differences between the two groups(with each contrast patient being matched to four controlpatients). There were 167 deaths in the study (38/2900 inthe contrast group and 129/11600 in the non-contrastgroup). Comparing patients who received CE with thosewho did not, there was no increase in mortality on thesame day (odds ratio [OR], 1.18 [95% CI, 0.82–1.17]; P =0.37) or on the next day (OR, 1.22 [95% CI, 0.91–1.64];P = 0.178). Subgroup analysis also revealed that there wasno same-day or next-day mortality difference betweenmechanically ventilated and non-ventilated critically illpatients.

In summary, CE is a safe and effective technique, even incritically ill patients, for whom its benefits greatly outweighany potential risks. While it is important to understand thetechnique’s limitations and safety profile, harm can also bedone by withholding a valid technique and thus making anincorrect diagnosis due to suboptimal imaging.

As for any clinical situation, the decision whether to use aparticular investigation (in this case, CE) in critically illpatients is based on the balance of risk to benefit on a case-by-case basis. The ability to obtain an accurate cardiacassessment using a non-invasive bedside test should besought in the critical care setting.

Contrast artefacts and limitations

CE can salvage a non-diagnostic unenhanced transthoracicechocardiogram. However, like all forms of imaging, it haslimitations and potential artefacts. As with any ultrasoundinvestigation, obtaining a satisfactory contrast image relieson the interaction between the agent and ultrasound. Ifthere is significant distortion of chest anatomy that preventsadequate exposure of the heart to ultrasound, the additionof contrast will not necessarily result in an improved ordiagnostic image. Contrast artefacts that can limit imagequality include basal attenuation, contrast swirling, lowconcentration and blooming. Attenuation of the far fieldcan occur, as contrast agent in the apical region can act as abarrier to ultrasound penetration into the mid and distalstructures. This can occur if the contrast agent is adminis-tered too quickly or the dose is too high. Contrast swirlingtypically occurs in the near field and is a manifestation ofbubble destruction. This can occur if the contrast agentdose or concentration is too low or if the mechanical indexis too high. There are two types of contrast blooming.Blooming during spectral Doppler imaging results in anindistinct spectral profile due to excessive concentration ofcontrast agent or gain settings. Blooming during two-

dimensional imaging can occur when the contrast agentconcentration within the LV cavity is too high, resulting inan indistinct endocardial border. These artefacts can usuallybe overcome once the operator gains experience in contrastimaging and is able to judge the correct concentration andadministration rate for particular imaging settings.

Contrast echocardiography in patients receiving cardiac mechanical support

Contrast microspheres are hydrodynamically labile struc-tures and are prone to destruction from mechanical forces.Even injection into a side port is not recommended, as theshear forces and turbulent flow result in a degree of bubbledestruction before any clinically useful imaging. Patientsreceiving cardiac mechanical support, such as those using aventricular assist device or undergoing ECMO treatment,are usually difficult to image with conventional TTE. Thesepatients could benefit from CE. However, there is a paucityof data on the feasibility and safety of CE in this clinicalsetting, and further research is required in this area.Increased bubble destruction (due to transit through theventricular assist device or ECMO chamber), coupled withnatural attrition, would be expected to result in reducedsignal persistence and hence reduced diagnostic imagingtime with each bolus dose.

In a case report describing CE use in a patient supportedon venoarterial ECMO,25 diagnostic images were obtainedwith contrast imaging, but with the anticipated reduction insignal persistence after each bolus dose. Figure 11A andFigure 11B show an apical four-chamber view before andafter contrast enhancement, respectively.

Future applications

Contrast echocardiography is a well accepted and approvedmodality for LVO. However, there are additional potentialapplications for CE, including the assessment of organperfusion (eg, cardiac and renal perfusion) and the targeteddelivery of gene therapy. Despite an increasing body ofsupportive evidence, no agent is currently approved for usein the perfusion setting. The use of contrast imaging toassess cardiac perfusion is referred to as myocardial contrastechocardiography. Contrast microbubbles have many prop-erties that make them potentially attractive as perfusionagents: they are haemodynamically inert, uniformly distrib-uted within the blood pool, do not rely on diffusion orextraction from the circulation for effect, remain entirelywithin the blood pool, and have the same intravascularrheology as red blood cells. Consequently, they have thepotential to act as pure blood flow tracers. There arenumerous clinical scenarios in which MCE may potentiallybe useful, including detection of acute coronary syndromes,

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detection of chronic coronary artery disease and assessmentof myocardial viability. By using specific perfusion modalities(such as flash destruction, replenishment and low-MI imag-ing), MCE could potentially be used to determine myocar-dial blood volume and myocardial blood flow.6,56,57

The ability to assess patients for myocardial viabilitywould hold particular promise in the critical care setting.Myocardial viability is a crucial component in patients withcoronary artery disease who are being considered forrevascularisation, be it percutaneously or surgically.58,59

However, for a critically ill patient in the ICU, the options formyocardial viability assessment are essentially non-existent.Conventional viability assessment using cardiac magneticresonance imaging, nuclear imaging techniques or dob-utamine stress echocardiography are not practically feasi-

ble, particularly in the setting of mechanical support of anytype. There is evidence to support the use of MCE forviability assessment,60-69 although it has not been evaluatedin the critical care setting. A bedside test of myocardialviability could have significant potential in this setting.

Conclusion

Echocardiography is a fundamental investigation used tomanage patients in the critical care setting. The information itprovides has a significant impact on treatment strategies, butsuboptimal image quality can often limit the accuracy orconfidence in the data obtained. Non-diagnostic TTE imagesmay be obtained in up to 25% of patients in the critical caresetting. However, with the advent of contrast microspheresand contrast-specific imaging modalities, there is now amethod available to convert these non-diagnostic imagesinto accurate and clinically useful scans. Contrast-enhancedTTE can provide an accurate, safe and rapid assessment of LVstructure, function and morphology. It can also help incardiac mass evaluation, vascular imaging and spectral Dop-pler enhancement. Research is ongoing regarding its role as amyocardial perfusion agent, and potential future applicationswithin this field include targeted delivery of gene therapy,myocardial perfusion imaging and contrast-enhanced three-dimensional echocardiography.

A recent consensus statement issued by the AmericanSociety of Echocardiography26 states that “the availability ofcontrast imaging in the ICU enhances overall efficiency,diagnostic accuracy and cost-effective patient managementand has no incremental risk for death compared with noncontrast echocardiography”. For patients in the critical caresetting with non-diagnostic TTE results, CE should now beat the forefront of a diagnostic algorithm.

Author detailsDavid G Platts, Senior Staff Specialist1,3

John F Fraser, Eminent Staff Specialist2,3

1 Department of Echocardiography, Prince Charles Hospital, Brisbane, QLD, Australia.

2 Department of Critical Care Medicine, Prince Charles Hospital, Brisbane, QLD, Australia.

3 Critical Care Research Group, Prince Charles Hospital, Brisbane, QLD, Australia.

Correspondence: david_platts@health.qld.gov.au

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Figure 11. Apical four-chamber images in a patient receiving venoarterial ECMO, performed to assess LVEF and to evaluate for LV thrombus

A: Conventional imaging.

B: The same view with contrast-enhanced imaging, showing no LV thrombus and clear endocardial definition for accurate calculation of the LVEF.

ECMO = extracorporeal membrane oxygenation. LV = left ventricular. LVEF = LV ejection fraction.

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Contrast agentsPharmacokineticsOther contrast agentsContrast-specific imagingContrast agent preparation and administrationContrast indications and clinical applicationsApplication of contrast LVO in critical careContrast agent safety and contraindicationsContrast artefacts and limitationsContrast echocardiography in patients receiving cardiac mechanical support

Future applicationsConclusionAuthor detailsReferences